Protein Persulfidation Protects Against Aging

Abstract

For couple of decades aging is believed to be a consequence of damages accumulated by increased production of reactive oxygen species (ROS). Opposite to that, dietary restriction attempts to extend life have been linked to increased H2S production. We hypothesized that reacting with sulfenic acids (formed by ROS) H2S would rescue cysteine residue by forming persulfides. Persulfides are better ROS scavengers and could form protein S-sulfonates that could be cleaved back by disulfide reductase to restore free thiolate. This rescue loop would thus prevent irreversible thiol hyperoxidation. Using dimedone switch method we could first show that persulfidation is a posttranslational modification that is evolutionarily conserved (bacteria, flies, worms, mice and humans). Then we could also observe that thioredoxin readily catalyzes the reduction of cysteine S-sulfonate, two orders of magnitude faster than the reduction of corresponding disulfide. The persulfidation levels/H2S producing ability positively correlated with the ability of yeast, worms and mammalian cells to resist stress caused by ROS. Persulfidation declines with aging in worms, rats and mice, due to the downregulation of H2S producing enzymes, but dietary restriction in mice and worms restores persulfide levels and improves their lifespan. Based on these data we suggest that persulfidation represents an evolutionarily conserved anti-aging mechanism.